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DOI 10.1378/chest.124.3.1175
2003;124;1175-1176Chest
Glenn D. Crater, Jr
Levalbuterol vs Racemic Albuterol
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2007Physicians. It has been published monthly since 1935. Copyright
CHEST is the official journal of the American College of Chest
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infection. Symptoms began 2 months after the beginning of
treatment with etanercept, which seemed early for the develop-
ment of disseminated MAC infection. Reports from the HIV
literature
3
derived from the early 1990s stated that the mean
period of time until the appearance of disseminated MAC infection
was at least 8 months after making the diagnosis of HIV. Another
observation seen was the distinct two-tiered improvement, which
was possibly not emphasized adequately with the original report.
2
A
clear improvement first occurred during the week immediately after
stopping etanercept therapy, with no additional clinical change
demonstrated until prednisone was added.
Inhibitors of tumor necrosis factor and corticosteroids have
been shown to impair defense mechanisms directed toward myco-
bacterial infection.
4,5
Even if immunity was restored after stopping
etanercept therapy, the effect was transient since prednisone was
implemented by week 4. Under these conditions, a spontaneous and
sustained remission of disseminated MAC would be unlikely. Ad-
mittedly, treatment with steroids can impact the illness severity of
mycobacterial infection, for which reason it is sometimes used as an
adjunct to antimicrobial therapy.
6
Complete resolution of the pa-
thology extending from mycobacterial disease would not be ex-
pected with prednisone alone, unless the Mycobacterium was linked
to hypersensitivity pneumonitis.
Our patient had no exposure to hot tubs or swimming pools,
which have been linked to MAC hypersensitivity pneumonitis.
7
Moreover, the case descriptions of this relatively new entity
appear to be comparable to extrinsic allergic alveolitis. A major
characteristic of extrinsic allergic alveolitis is that the pathology is
limited to lung tissue.
8
For our patient, the granulomatous
inflammation was systemic, seen in specimens from both lung
and skin biopsies. The combination of systemic pathology with no
inhalation exposures strongly argues against a diagnosis of myco-
bacterial hypersensitivity pneumonitis.
In summary, our case is unique to those reporting MAC
hypersensitivity pneumonitis in that the inflammation was sys-
temic. Discriminating between disseminated MAC infection and
drug-induced injury can be more of a challenge. In retrospect,
blood cultures may have been helpful and are recommended for
future cases presenting in a similar manner. The temporal
features, along with the response to the therapeutic interven-
tions, favor a diagnosis of etanercept-induced lung injury. The
MAC isolated in our case is more likely to represent colonization.
Laura Peno-Green, MD, PhD, FCCP
Marietta Pulmonary Medicine
Marietta, GA
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Laura Peno-Green, MD, PhD, FCCP, Mari-
etta Pulmonary Medicine, 55 Whitcher St, Suite 420, Marietta,
GA 30060-6947; e-mail: laura.peno-green@wellstar.org
References
1 Casey MB, Tazilaar HD, Myers JL. Noninfectious lung
pathology in patients with Crohn’s disease. Am J Surg Pathol
2003; 27:213–221
2 Peno-Green LA, Lluberas G, Kingsley T, et al. Lung injury
linked to etanercept therapy. Chest 2002; 122:1858–1860
3 Mandell GL, Bennett JE, Dolin R. Principles and practice of
infectious diseases. 5th ed. Philadelphia, PA: Churchill Liv-
ingstone, 2000; 2621
4 Bermudez LE, Young LS. Tumor necrosis factor, alone or in
combination with IL-2, but not IFN-␥, is associated with
macrophage killing of Mycobacterium avium complex. 1988;
140:3006–3016
5 Sathe SS, Tsigler D, Saral A, et al. Pentoxifylline impairs
macrophage defense against Mycobacterium avium complex.
J Infect Dis 1995; 172:863–866
6 Dorman SE, Heller HM, Basgoz NO, et al. Adjunctive
corticosteroid therapy for patients whose treatment for dis-
seminated Mycobacterium avium complex infection has
failed. Clin Infect Dis 1998; 26:682–686
7 Embil J, Warren P, Yakrus M, et al. Pulmonary illness
associated with exposure to Mycobacterium-avium complex
in hot tub water. Chest 1997; 111:813–816
8 Fraser RS, Pare´ PD, Coleman N, et al. Diagnosis of diseases
of the chest. 4th ed. Philadelphia, PA: WB Saunders, 1999;
2361–2375
Levalbuterol vs Racemic Albuterol
Science or Drug Company Propaganda?
To the Editor:
With regard to the article by Truit et al (January 2003),
1
I
would like to raise the following concerns: this was a retrospective
study; the placebo factor and other confounding factors were not
taken into account; other differences in treatments were not
considered; and sicker patients were enrolled in the control
group.
In retrospective studies, care must be taken to ensure that
nothing changed between the two treatment groups. During this
study, the pressure to treat patients in the outpatient setting may
have changed, and new medications were introduced. Addition-
ally, the physicians changed the protocol, suggesting that they
believed the medication was safer and more effective, and
perhaps was influencing them to send patients home earlier.
Furthermore, the authors admit that they cannot track other
treatments that may have changed.
When a therapy is changed in the “real world,” there are always
questions from patients. It would be interesting to know how this
change was presented to the patients. I doubt that my patients who
are accustomed to treatment every 4 h would graciously accept a
reduction of those treatments by half without some explanation.
Another concern is reference 6, a letter that was published in
Lancet, which is quoted as evidence that S-albuterol is potentially
dangerous. Before we discard a drug that is cheap, safe, and
effective, we should use articles that have been peer-reviewed
and the data in which are reproducible.
In regard to the patients in the study, it appears that asthma
patients were overrepresented when racemic albuterol was used
(28% vs 18%, respectively). Also, these patients had a lower FEV
1
at hospital admission (44.6% predicted vs 48.6% predicted,
respectively), suggesting that they were sicker and required more
interventions.
Furthermore, despite receiving albuterol on hospital discharge,
the authors cite a reduction in 30-day readmission rates for the
levalbuterol group. Are the authors suggesting that the effects of
the drug last for 30 days? Notably, none of the asthmatic patients
in the racemic albuterol group required readmission!
This article may question the dosing of albuterol every 4 h.
Perhaps dosing every 8 h, in some patients, would be just as
effective. And perhaps the best treatment is bronchodilator use
only when a patient is symptomatic as a result of bronchospasm.
Glenn D. Crater, Jr., MD, FCCP
East Tennessee Pulmonary Associates
Oak Ridge, TN
Dr. Crater is a reviewer for CHEST and is in the Speakers
Bureau for GlaxoSmithKline.
www.chestjournal.org CHEST / 124/3/SEPTEMBER, 2003 1175
Copyright © 2003 American College of Chest Physicians
at GlaxoSmithKline on August 11, 2009www.chestjournal.orgDownloaded from
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Glenn D. Crater, Jr., MD, FCCP, East
Tennessee Pulmonary Associates, 200 New York Ave, Suite 210,
Oak Ridge, TN 37830; e-mail: gcmd@alumni.wfu.edu
Reference
1 Truitt T, Witko J, Halpern M. Levalbuterol compared to
racemic albuterol: efficacy and outcomes in patients hospital-
ized with COPD or asthma. Chest 2003; 123:128–135
Levalbuterol Is Not More Cost-
Effective Than Albuterol for COPD
To the Editor:
In a recent issue of CHEST, Truitt et al (January 2003)
1
claimed that their retrospective chart review demonstrated that
“levalbuterol afforded clinical and pharmacoeconomic advan-
tages over racemic albuterol” in the treatment of hospitalized
patients with COPD and asthma. The primary end point of the
study was the total number of nebulizer treatments required.
However, the target care path that was in operation during the
historical cohort required albuterol to be administered every 4 h
(six treatments per day), while in the current cohort levalbuterol
was administered every 8 h (three treatments per day). Thus, the
statistically significant difference in the primary end point was a
result of differences in the care plans. There were no statistically
significant differences in the number of extra treatments required
by either cohort. Surprisingly, the reviewers missed this fatal flaw
in the study design.
The combination of more treatments, by design, and an
artificially higher cost basis for albuterol resulted in a spurious
statistical difference for the total cost of nebulizer therapy. They
used the “average wholesale price” (AWP), but no hospital
pharmacy ever pays the AWP. For many hospitals, the acquisition
cost of racemic albuterol is around $0.32 per 2.5-mg dose
compared to $1.82 per 1.25 mg for an equivalent dose of
levalbuterol (ie, a 5.7-fold difference). In contrast, the AWP for
the two products are $1.21 and $2.08, respectively (a 1.7-fold
difference).
2
No conclusions can be drawn about clinical advantages since
the treatments were not administered in a double-blind random-
ized manner. Moreover, in patients with COPD (about 80% of
the patients), FEV
1
did not significantly increase from hospital
admission to hospital discharge in either cohort. In such patients,
it is possible that dosing every 8 h with albuterol would be as
effective as dosing every 4 h since these patients show little
response to bronchodilators. Also, we are incredulous about the
statement that levalbuterol “appeared to have a more prolonged
therapeutic effect.” The basis for this statement was a difference
in the hospital readmission rate, but since this was a retrospective
chart review, other factors such as differences in hospital dis-
charge medication (data not presented) may have affected this
end point.
Last, “not significant” was designated as p ⬎0.1 when the
convention is p ⬎0.05. As a consequence, the authors inferred
that important pharmacoeconomic end points were different
when they were not statistically different. For example, the
authors state that those treated with levalbuterol “had shorter
lengths of hospital stay” and “decreased costs for hospitalization,”
but the p values for these end points for patients with COPD
were 0.07 and 0.11, respectively.
We conclude that the differences between albuterol and
levalbuterol in this study were a result of differences in the
number of treatments required by the care plan, invalid cost
calculations, and the emphasizing of numerical differences that
were not statistically significant by conventional criteria.
Leslie Hendeles, PharmD
Abraham Hartzema, PhD
University of Florida
Gainesville, FL
Neither author has received money in the last 3 years from a
competitor of Sepracor, the manufacturer of Xopenex.
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Leslie Hendeles, PharmD, Professor, Phar-
macy and Pediatrics, University of Florida, Gainesville, FL
32610-0486
References
1 Truitt T, Witko J, Halpern M. Levalbuterol compared to
racemic albuterol; efficacy and outcomes in patients hospital-
ized with COPD and asthma. Chest 2003; 123:128–135
2 Medical Economics Inc. 2001 drug topics red book.
Montvale, NJ: Medical Economics Inc, 2001; 170, 571
To the Editor:
We welcome the opportunity to respond to the letters to the
editor in CHEST regarding our recent article (January 2003).
1
We agree with Dr. Crater that in retrospective studies, care must
be taken to ensure that treatment groups are fully comparable.
This is why we compared treatment with racemic albuterol and
levalbuterol among patients with the same diagnosis codes, who
had been treated at the same hospital, by the same pulmonolo-
gists, and during the same months of two sequential years.
Furthermore, as indicated in the footnote to Table 1 of our
article, there were no significant differences in age, gender
distribution, racial distribution, percentage of patients hospital-
ized in the past year, steroid use, or hospital admission and
discharge FEV
1
and FVC levels between the levalbuterol and
racemic albuterol groups. We also acknowledged and addressed
the limitations of the study in the “Discussion” section of our
article, including the limitations associated with a retrospective
study performed at a single institution.
Dr. Crater expressed concern that one of the references cited
in the manuscript (Reference 6) is a letter that was published in
Lancet. However, research letters published in Lancet undergo
peer review prior to publication. Furthermore, multiple other
references cited in this article (References 7 to 14) present
evidence from in vitro and animal studies of the detrimental
effects of (S)-albuterol.
It is also correct that individuals with asthma comprised a
greater proportion of those who received racemic albuterol
compared with those who received levalbuterol (28% vs 17.9%,
respectively). However, separate analyses were performed com-
paring patients with asthma to those with COPD in the two study
populations. Length of hospitalization was 1 day less among
patients with COPD and 1.2 days less among patients with
asthma when treated with levalbuterol, although these differ-
ences were not significant (p ⫽0.097 and p ⫽0.07, respectively).
The reduction in the need for nebulizer treatments among
patients treated with levalbuterol vs those treated with racemic
albuterol was greater for patients with asthma than for patients
with COPD. Furthermore, as presented in Table 4, multivariate
regressions controlling for diagnosis (ie, asthma vs COPD)
indicated statistically significant impacts of levalbuterol treatment
1176 Communications to the Editor
Copyright © 2003 American College of Chest Physicians
at GlaxoSmithKline on August 11, 2009www.chestjournal.orgDownloaded from
DOI 10.1378/chest.124.3.1175
2003;124; 1175-1176Chest
Glenn D. Crater, Jr
Levalbuterol vs Racemic Albuterol
August 11, 2009This information is current as of
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